Hospital Medicine

West-Nile encephalitis

West Nile encephalitis

I. What every physician needs to know.

West Nile virus (WNV) is a mosquito-transmitted arbovirus of the family Flaviviridae; this family also includes the etiologic agents of yellow fever, dengue, and Zika. Several bird species serve as normal reservoirs for the virus, with incidental human transmission mediated by Culex species mosquitoes that feed on birds, humans, and other mammals. WNV was first isolated from the West Nile region of Uganda in 1937 and was first diagnosed in North America in New York City in 1999.

WNV is now widely distributed across North America. Transmission has been reported in every state except Alaska and Hawaii; local outbreaks can occur. Peak transmission occurs between June and September, although cases are reported whenever mosquitoes are active. In the peak reporting year of 2003, 9,862 cases were reported. 5,674 cases were reported in 2012 representing the highest number of reported cases since 2003 (www.cdc.gov/westnile).

Less than 1 percent of WNV infections produce neuroinvasive disease; 80 percent are asymptomatic and 20 percent manifest as West Nile fever. The vast majority of cases are transmitted by mosquito bite, but cases have been rarely transmitted by organ transplantation, blood product transfusion, and from mother to infant during pregnancy, delivery, or breast feeding. Human-to-human transmission and/or sexual transmission have not been described.

After inoculation, WNV replicates in cutaneous dendritic cells and regional lymph nodes, then viremia generally occurs within 2 weeks. Twenty percent of people get West Nile fever, with symptoms of fever, headache, rash, body aches, joint pains, vomiting, and diarrhea. Most people recover completely, though the fatigue can persist for weeks. One percent of people (usually people age > 60 years or with immunocompromising conditions or medical co-morbidities) develop neuroinvasive disease, (meningitis or encephalitis) with headache, fever, neck stiffness, altered mental status, tremors, seizures, or paralysis.

Variations in the host’s immune response mediate clinical manifestations of infection. Age >60 years is the most prominent risk factor for neuroinvasive disease, despite uniform viral attack rates for all ages, but the biological basis for age-related risk is not clearly defined.

There is no proven antiviral therapy for WNV encephalitis at this time and no licensed vaccines for people. Treatment is supportive.

II. Diagnostic Confirmation: Does your patient have West Nile virus?

WNV neuroinvasive disease (meningitis or encephalitis) is diagnosed by the detection of WNV ribonucleic acid (RNA) by polymerase chain reaction (PCR) or WNV immunoglobulin M (IgM) in cerebrospinal fluid (CSF) in a patient with compatible clinical symptoms and possible exposure (i.e. during mosquito season). West Nile infection can also be diagnosed by detection of WNV RNA or IgM in serum, though this will not differentiate between infection and neuroinvasive disease. Clinical findings do not predictably differentiate WNV from other encephalitides, although some findings may suggest WNV infection, as outlined below. Detection of West Nile IgG, as opposed to IgM, indicates either convalescence or prior exposure. WNV IgG persists for years or decades after infection.

WNV IgM generally appears within 3-8 days after onset of symptoms, and can persist for up to 90 or more days. Serum or CSF collected in the first 8 days of illness may not yet have detectable IgM, and should be sent for PCR. A patient with compatible symptoms, history of possible exposure, and a positive PCR can be presumed to have WNV infection.

Because antibodies to other Flaviviruses (dengue, Zika, yellow fever virus, etc.), can cross-react with WNV IgM or IgG, a specimen positive for these antibodies should be sent to the state public health laboratory or the CDC for specific tests for neutralizing antibodies to confirm the diagnosis. CSF and serum IgM and PCR testing are available through state public health laboratories.

A. History Part I: Pattern Recognition:

The usual incubation period is 2-6 days, but it may extend to 14 days after inoculation. Symptomatic WNV infection may present as West Nile fever or West Nile encephalitis.

West Nile fever presents as a systemic febrile illness with headache, retroorbital and back pain, arthralgias, and myalgias. Other symptoms and signs variably reported include vomiting, diarrhea, cough, and sore throat. Maculopapular rash on the chest, back, and arms, which has been described in 25-50 percent of cases, may suggest a lower risk of neuroinvasive disease, although the reasons are unclear. Lymphadenopathy was noted in early outbreaks but is less frequent now.

Neuroinvasive WNV infection presents with a 1-7 day prodrome of fever, followed by the development of neurologic symptoms. The incidence and severity of neuroinvasive disease is significantly higher in the elderly. In recent outbreaks, encephalitis has been described in two-thirds of patients with neuroinvasive disease and meningitis in a third. Encephalitis cases predominate in adults, while meningitis is seen more frequently in infected children. Encephalitis may or may not be associated with signs of meningeal irritation.

Manifestations of WNV encephalitis range from mild confusion to coma and death. Myoclonus and Parkinsonian symptoms, such as bradykinesia, tremor, and rigidity, are often seen, suggesting WNV disease in a compatible epidemiologic setting. Seizures were more commonly noted in early WNV case series than in recent reports.

More recent outbreaks have included cases of myelitis with viral anterior horn neural invasion, leading to polio-like flaccid paralysis, which is often asymmetric. Myelitis may be associated with meningitis or encephalitis but is not invariably so. Bulbar involvement with attendant cranial nerve palsies may be seen, and when in conjunction with quadriplegia, it is associated with high risk of respiratory failure.

B. History Part 2: Prevalence:

The primary risk factor for neuroinvasive WNV disease is age > 60 years; invasive disease risk rises steeply in the seventh decade and thereafter. It is not clear whether this enhanced susceptibility is due to immune senescence alone or whether other age-related CNS changes increase risk. Persistent neuroinvasive disease has been reported in immunocompromised patients.

C. History Part 3: Competing diagnoses that can mimic West Nile virus.

The differential diagnosis of WNV neuroinvasive disease includes other infectious and non-infectious causes of encephalitis. The challenge is to identify treatable causes of encephalitis in a timely manner, as there is limited clinical differentiation among the multiple potential etiologies, particularly in the early stages of illness. Over half of encephalitis cases in North American case series remain idiopathic.

In an outbreak setting, clinical suspicion for WNV will, of course, be heightened. In non-epidemic settings, epidemiologic features that raise concern for WNV infection include:

local public health reports of bird die-offs or WNV identification in mosquito surveillance;

onset of illness in mid or late summer;

patient history of extensive outdoor activities.

The 2008 Infectious Diseases Society of America (IDSA) published guidelines for evaluation and management of encephalitis.

D. Physical Examination Findings.

Chorioretinitis and other ophthalmologic manifestations, including uveitis, vitritis, vasculitis, and vitreal hemorrhage, are well described, although their frequency is uncertain. Pancreatitis, myocarditis, hepatitis, rhabdomyolysis, and orchitis have also been described.

The clinical spectrum of neuroinvasive WNV includes meningitis, meningoencephalitis, and myelitis. Myoclonus and Parkinsonian signs of basal ganglia damage, such as increased tone, rigidity, resting tremor, and bradykinesia, are often seen. Asymmetric polio-like flaccid paralysis is seen in cases of myelitis. Involvement of one or limbs, with or without bulbar involvement, may be noted.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Detailed recommendations for the diagnostic laboratory evaluation of encephalitis were published by the Infectious Diseases Society of America in 2008 (PUBMED:18582201). The selection of tests to perform is determined by patient-specific epidemiologic and clinical features, generally in consultation with infectious disease or neurology specialists.

Viral detection of WNV in the CSF by PCR is positive in less than 60 percent of patients but should be sent if available. Serum IgM antibody testing is positive in more than 95 percent of patients tested 7-10 days after illness onset. CSF IgM antibody should be assayed, as it may appear before serum IgM.

Routine blood work results are not specific to WNV infection. Leucocytosis or leucopenia may be seen, and persistent lymphopenia (<10%) has been noted by some observers. Hyponatremia may be present consequent to CNS inflammation.

CSF typically shows a white blood cell count of ~200-250 cells/cubic millimeter with a modest elevation of protein. In less than 5 percent of cases, acellular fluid may be seen. A polymorphonuclear predominant differential has been described in approximately 40 percent of patients. Similar spinal fluid profiles are seen in meningitis and encephalitis cases.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

MRI, the most sensitive neuroimaging test in suspected cases of encephalitis, should be performed. CT with and without contrast may be performed if MRI cannot be obtained, although its sensitivity for WNV specific abnormalities is low. In about a third of cases of WNV encephalitis, T2-weighted and FLAIR images may show hyperintense lesions in the basal ganglia, substantia nigra, and thalami. These changes provide a neuroanatomic correlate to the extrapyramidal findings on examination. Brain stem and spinal cord involvement may be also be seen in association with clinical findings.

Electroencephalogram (EEG) in West Nile patients typically shows diffuse slowing, a finding which is not specific for WNV infection. However, the presence of seizure activity on EEG may help differentiate mental status changes that are in part or whole due to non-convulsive epilepsy from those of CNS infection alone.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None.

III. Default Management.

Management of WNV encephalitis is largely supportive, as there is no proven antiviral therapy. Trials of interferon alfa-2b, ribavirin, and intravenous immunoglobulin have been unsuccessful to date. There is no approved vaccine for people.

A. Immediate management.

WNV encephalitis may be strongly suspected in an outbreak situation or when suggestive clinical and epidemiologic features are present.

Definite diagnosis of WNV on admission is unlikely given the inherent delays in obtaining serologic and culture data. Therefore, empiric acyclovir for herpes simplex (HSV) encephalitis is indicated, as the clinical outcome for HSV encephalitis is determined by how promptly treatment is initiated.

Empiric antimicrobial treatment for bacterial meningitis is also indicated if the clinical presentation or spinal fluid formula is not clearly consistent with a viral etiology (i.e., if a significant percentage of polymorphonuclear leucocytes or hypoglycorrhachia is present). Although polymorphonuclear leucocytes may be seen with viral CNS infections, including WNV and HSV, their presence raises concern for an underlying bacterial process.

Hypoglycorrhachia has been described with viral processes, including WNV. However, its presence, particularly if severe, suggests a bacterial, fungal, or neoplastic etiology. Listeria meningitis may be of particular concern, as it is more commonly seen in patients over age fifty and may be associated with rhombencephalitis. Complete guidelines for empiric treatment of bacterial meningitis were developed by the IDSA in 2004 (PUBMED:15494903).

Initial therapy of suspected cases also includes the following general measures:

Provide close oversight by nursing, with sitter or family present if there is a fall risk.

Where possible, avoid pharmacologic agents that will exacerbate delirium.

B. Physical Examination Tips to Guide Management.

An erythematous maculopapular rash accompanying encephalitis or meningitis symptoms during mosquito season should suggest West Nile infection, but is not definitive. Patients with encephalitis should have a daily neurologic examination performed to assess their progress. The lungs should be monitored for signs of aspiration, and dependent areas should be checked routinely for early bedsores if immobility is prolonged. Patients who receive antibiotic therapy should be monitored for signs or symptoms of toxicity, such as rash or diarrhea.

Renal function and electrolytes should be monitored every 24-48 hours to assess for metabolic disturbances, such as hyponatremia, that may exacerbate neurologic abnormalities. Complete blood count should be checked every 48-72 hours as part of routine surveillance for nosocomial infections and drug toxicity.

D. Long-term management.

In addition to routine management, intermediate and long-term management issues include nutritional status, as interim Dobhoff or gastrostomy tube may be necessary to support ongoing nutritional needs, and physical, occupational, and speech therapy as determined by clinical progress and neurologic deficits.

E. Common Pitfalls and Side-Effects of Management

As the initial presentation of meningoencephalitis is often nonspecific, of greatest concern in initial management is failure to consider and test for treatable pathogens.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Monitor for deterioration in mental status compromising airway or alimentation. Monitor for seizures.

B. Anticipated Length of Stay.

Variable depending on severity of infection: from days to weeks.

C. When is the Patient Ready for Discharge.

Patients may be discharged to home, a subacute facility, or a unit specializing in neurologic rehabilitation (e.g. speech, occupational, gait therapy) depending on the degree of improvement while in acute care and prognosis for recovery.

D. Arranging for Clinic Follow-up

The time and frequency of post discharge visits to primary care, neurology, and therapy will be determined by the individualized discharge care plan.

1. When should clinic follow up be arranged and with whom?

See above.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Routine labs to ensure resolution or stability of any notable blood abnormalities (e.g. sodium level in cases associated with hyponatremia).

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

Blood work to follow up on any remaining abnormalities noted while under acute care (e. g. sodium level in cases associated with hyponatremia).

E. Placement Considerations.

Disposition will largely be determined by the trajectory of improvement in the patient’s mental status and extent and nature of residual neurologic deficits. If the patient requires rehabilitation at discharge the hospitalist, in conjunction with speech therapy, physical therapy, occupational therapy, and care management should determine whether a unit specializing in neurologically impaired patients is available and/or appropriate. The ability of the patient to meet his/her nutritional requirements and need for PEG placement should also be determined before discharge.

F. Prognosis and Patient Counseling.

WNV encephalitis is associated with a poor prognosis in severely affected patients and in the elderly. A case fatality rate of approximately 14 percent in encephalitis cases has been reported. Case fatality rates are higher for encephalitis or flaccid paralysis than for meningitis. Data regarding long-term prognosis in neuroinvasive disease is conflicting: reported one-year outcomes have ranged from full recovery in patients surviving hospitalization to persistent motor (muscle weakness) and neuropsychological (memory loss and other) deficits in one-third to two-thirds of patients.

Incomplete recovery is the norm for patients with myelitis and flaccid paralysis. Improvement may occur, particularly in the first several months, but significant residual deficits are typical. Bulbar involvement and quadriplegia are associated with a poor prognosis.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

No Joint Commission on Accreditation of Healthcare indicators related to WNV management.